Sock's Rheumatoid Arthritis Page 1:
Treatment
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A longitudinal treatment plan needs to be developed with the patient. The discussion should address disease prognosis and treatment options, taking into account the costs,adverse effects,expected time for response, and monitoring requirements of pharmacologic agents,in addition to the patient's preferences.
 
Expectations for treatment and potential barriers to carrying out the recommendations should be discussed. Patient education is critical to engaging the patient in an effective partnership for managing the disease
 
The aggressiveness and timing of the treatment program require an assessment of prognosis. Poor prognosis is suggested by earlier age of onset,high titer of RF,elevated ESR,and swelling of  >20 joints.
 
Extra-articular manifestations of RA,including rheumatoid nodules, Sjogren's syndrome,episcleritis and scleritis, intestitial lung disease, systemic vasculitis,and Felty's syndrome,indicate a worse prognosis. These manifestations may vary in severity and significance.
 
Treatment of RA----Nonsteriodal anti-inflammatory drugs (NSAIDs). The initial drug treatment of RA usually involves the use of NSAIDs to reduce joint pain and swelling and improve function. NSAIDs have analgestic and anti-inflammatory properties but do not alter the course of the disease or prevent joint destruction.
 
Goal: Symtomatic relief of pain and swelling. Limitation: Unlikely to prevent damage. Factors for selecting drugs: Dosing regimen, efficacy, tolerance, costs ,patient age,presence of comorbid disease(s), patient preferences and concurrent drugs. Monitoring efficacy--Symptoms of active synovitis. Monitoring  of toxicity is to be performed.   
 
There are significant individual effects  in efficacy among the many NSAIDs,and there are some differences in the incidence of side effects.  Salicylates are inexpensive, and blood levels may be measured to confirm that there has been an adequate anti-inflammatory dose and to assess compliance. Analgesic effects of salicylates and NSAIDs are prompt in onset, but reduction of inflammation may take up to 1-2 weeks or longer.
 
Patients with NSAID-induced GI intolerance or toxicity may require the concomitant use of GI-protective agents (misoprostal,cytotec etc.). There are newer NSAIDs such as Vioxx and Celebrex--Cox-2 inhibitors available that are designed to lessen GI tolerance.
 
Disease-modifying anti-rheumatic drugs (DMARDs). All patients whose RA remains active despite adequate treatment with NSAIDs are candidates for DMARD therapy. (NSAID and DMARD are used together). Active RA may lead to irreversible joint damage even in the early months of the disease,while NSAIDs and glucocorsteriods may alleviate symptoms,joint damage may occur and progress.
 
DMARDs have the potential to reduce or prevent joint damage, preserve joint integrity and function,and, ultimately:to reduce the total cost  of health care and maintain economic productivity of the patient with RA.
 
 Goal: Remission or optimal control of inflammatory joint disease. Limitations: May not prevent damage in spite of apparent clinical control-may not have lasting efficacy-may not be tolerated to toxicity.
 
Factors for selecting drugs Convenience and cost of medication and monitoring of toxicity-risk of adverse reactions,including frequency and seriousnss.-physician estimate of efficacy and disease prognosis. Toxicity must be monitored.
 
Glucocorticoids: Low dose oral glucocorticoids ( <=10 mg predisone or equivalent) and local injections of glucocorticoids are highly effective for relieving symptoms in patients with active RA. Low-dose gluco-corticoids appear to slow the rate of of joint damage.
 
The adverse effects  of systemic glucocorticoids,especially when taken in higher doses for extended periods of time,limit their use,however. When administered by an experienced physician glucocorticoid injection of joints is relatively safe,and effective.
 
Injecting one or a few of the most involved joints in a patient early in the course of RA may provide local,and even systemic benefit. The effects are sometimes dramatic, but may be temporary.  A patient who has flares in one or more joints can be treated successfully by injection of the flaring joint or joints,without requiring a major change in the  prescribed regimen.
 
Low-dose oral glucocorticoids may benefit the patient during the period before a DMARD has gained its full effect and when the disease is severe enough to affect the patient's function,sleep,or ability to work.
 
For patients receiving systemic glucocorticoids who exibit stable or improving disease,tapering of the doseage (slowly and incrementally) and eventual discontinuation of the medication  should be attempted ("bridge therapy").
 
Even if inflammation is successfully controlled or eliminated with medication, patients with chronic RA may be symptomatic from joint damage. If,in spite of optimal medical treatment,the patient has unacceptable pain and/or limitation of function because of structural damage,surgery should be considered. Surgery is not for everyone, however,and the decision should be made after careful consideration by patient and doctor:
 
Joint replacement-- This is the most frequently performed surgery for RA,and it is done primarily to relieve pain and improve or preserve joint function. Artificial joints are not always permanent and may eventually have to be replaced.This may be a issue for younger people. Upgrade and research into superior longer-lasting implants is on-going.
  
Tendon recontruction: RA can damage and even rupture tendons,the tissues that attach muscle to bone.This surgery,which is used most frequently on the hands,reconstructs the damaged tendon by attaching an intact tendon to it.This procedure can help to restore function, especially  if the tendon is completely ruptured.
 
Synovectomy: in this surgery,the doctor actually removes the inflamed synovial tissue. Synovectomy by itself is seldom performed now because not all of the tissue can be removed,and it grows back Synovectomy is done as part of reconstructive surgery,especially tendon reconstruction.
 
Essential component of management include:
 
1) Establishment of the diagnosis of RA (versus other forms of polyarthritis).
 
2) Systemic and regular evaluation of disease activity. (monitoring)
 
3) Patient education/rehabilitation interventions and initial treatment with NSAIDs.
 
4) Use of DMARDs. (early)
 
5) Possible use of local or low-dose oral glucocorticoids.
 
6) Minimization of the impact on the individuals's function.
 
7) Assessment of the adequacy of the treatment program and general health maintenance.
 
The course of rheumatoid arthritis  cannot be predicted in a given patient. Several patterns have been described:
 
*A spontaneous remission particularily in the seronegative patient (mild RA) within the first 24 months of symptoms (less than 10%).
 
*Recurrent explosive attacks followed by periods of quiescence,most commonly in the early phases.
 
*The usual pattern of persistant and progressive disease that wanes and waxes in intensity.
 
*There is mild-prominent stiffness-moderate-severe RA patients.
 
*Some patients will have extra-articular features associated with the disease that can affect the whole body.
 
*The pattern of disease activity,severity and disease progression will be individualized in most patients -this also applies to medication and therapy.
 
Disability is higher among patients with RA with 60 % being unable to work 10 years after the onset of disease. Recent studies have demonstrated an increased mortality in rheumatoid arthritis patients. Median life expectancy was shortened an average of 7 years for men and 3 years for women compared to controlled populations in more than 5000 patients with RA from four centres.
 
The mortality rate was two times greater than in the control population. Patients at risk for shortened survival are those with with systemic extra-articular involvement,low functional capacity,low social-economic status,low education and predisone use,according to the study.
 
Studies often have flaws-I have  some reservations about social-economic-low-education factors.

Rheumatoid arthritis usually starts gradually,but it can start suddenly in some. You might feel tired and achy,like you have the flu. Most people feel pain and stiffness in one or more joints,usually the hands,wrists,or feet. The joints may not be swollen at the beginning but will probably start to swell within a couple of months.
 
The joints pain almost always occurs in symmetrical joints,i.e.,the same joints on both sides of the body. E.G.,you might feel pain in both wrists or in the same finger on both hands. This is the usual case. Some people do not het joint pain right away,they just feel stiff all over,especially when they get up in the morning. The stiffness usually lasts 1 hour or more,others say the stiffness never goes away.
 
Other patients feel achy and stiff,particularily in the hips and shoulders,and this may continue for weeks or months before the joints start to swell-feel warm (inflammation ). This course  occurs more in older patients and may be confused with a disease called polymyalgia rheumatica.
 
Other people have swollen joints that are not painful at onset. There is much variation in the symptoms of rheumatoid arthritis and that also applies to patient efficacy of medication. One drug will work wonders for one patient and do nothing for another.
 
Side effects follow a similiar pattern in some  patients. However,a symmetric painful series of joints particularily in the hands,feet,and wrists is the most common presentation of this disease.
 
In some people,the joints are painful and swollen,then they get better,then worse again. RA can also,but very rarely,be asymmetric,i.e.,it can occur in a joint on one side of the body but not in the other side corresponding joint on the other side. Eventually,even in these people,the joints on the other side is also affected.-the disease becomes symmetric,the typical course of rheumatoid arthritis.
 
It was traditionally taught that 70-80% of RA patients could be controlled with NSAIDs alone. These NSAIDs were given on the false premise that most people with time will go into remission. Second-line drugs were considered "highly toxic" and were reserved for those patients who could not be controlled by the first-line drugs. It is now,well established,that spontaneous remission are not common and that early treatment with DMARDs is essential.
 
Dramatic changes have occurred in the treatment of RA and other inflammatory arthritis. Early aggressive treatment,the continuous use of DMARDs and the use of combinations of DMARDs to eradicate inflammation have become the accepted standard treatment. DMARDs can modify the natural course of rheumatic disease by preventing or delaying cartilage and bone destruction.
 
The effect of these agents is 2-fold by controlling joint inflammation,they provide symptomatic relief of pain,swelling and stiffness,and by preventing cartilage and bone destruction,they reduce joint damage and subsequent disability. The latter effect distinguishes this class of agents from other drugs such as NSAIDs.
 
The importance of treating RA early cannot be overemphasized. There is a window of opportunity for good control of the disease and prevention  of joint damage early in the course of the illness. Irreversible erosion can be seen on x-ray films within the first 1-2 years after the onset of the disease,and even earlier using magnetic resonance  imaging. Delays in treatment as short as 8-9 months have been associated with significantly damage and disability at 3 years and 5 years of follow-up.
 
Current recommendations include starting DMARD therapy as soon as the diagnosis of RA has been established. This means after 6 weeks of inflammation despite treatment with anti-inflammatory drugs. The aim of therapy is no longer simply to control the symptoms at a level of comfort that is satisfactory to the patient but also to eradicate inflammation,and thus have a greater impact on the associated disability. 
 
More aggressive therapy means continuous use of DMARDs, increasing the doseage to maximum tolerated or recommended until miminal or no inflammation is achieved,switching to a different DMARD  if no benefit is obtained after a trial at the maximum dose for an appropriate duration,and using combination therapy. Although DMARDs are potentially toxic,,their skillful use by a experienced clinician can help prevent problems. The incidence of serious side effects in long-term studies is rare.
 
Consultation with a rheumatologist is desirable before initiating DMARD treatment. It is important to have a definite diagnosis of RA before beginning DMARD therapy to avoid exposing patients to the risk of serious side effects for a benign transient arthritis.
 
The trend toward earlier and more aggressive treatment is not limited to RA. It has also shown to affect the prognosis of other rheumatic diseases,such as lupus nephritis,polymyositis,dermatomyositis and vasculitides.
 
Because a respose may not be observed for up to several months after DMARD therapy is started,it is important to offer support to patients during the waiting period. One or more intra-articular corticosteriod injections may be beneficial in alleviating the symptoms of joint inflammation. Alternatively low-dose predisone administered orally may be prescribed as "bridging therapy" until the effects of the second-line agent is felt.
 
Exercise helps lessen the symptoms of RA and can make you feel better overall. Appropriate and moderate stretching and strengthening will help relieve the pain,and keep the muscles,and tendons around the affected joint flexibile,and strong. Low impact exercises like swimming, walking,water aerobics,and perhaps stationary bicycling (if the knee is affected consult your doctor) can all reduce pain while maintaining strength, flexibility,and cardiovascular function
 
Physical therapists (preferably trained in rheumatic disease treatment) can teach you other techniques to manage the pain,and restore joint motion,and muscle strength. With the aid of properly trained occupational  therapists,they can assist the patient  in maintaining optimal function at work,in the home,and during leisure activities. There are also nurses  specifically trained in rheumatic diseases.
 
Patients may be referred to physiotheraphy and occupational therapy for treatments such as icing,the applying of wax and ultrasonography to reduce the symptom of inflammation. They may be referred to the Arthritis Self-Management Program.or other educational programs, offered by the Arthritis Society of Canada (http://www.arthritis.ca/) and others,to help them understand their disease and,thus,improve their ability to cope with symptoms. Patients must be made aware of the need for monitoring. The incidence of serious side effects is markedly reduced with regular monitoring,because adverse effects are more likely  to be discovered before serious serious or irreversible consequences arise.
 
Despite the long list of side effects which intimidates patients,long-term series of RA patients treated with DMARDs have found that serious side effects are rare.
 
When counselling a patient who express concern about potential side effects,it is also important to remind him or her of the consequences of the alternative, doing nothing will result in irreversible disability,progressive joint damage and premature death. Drugs such as methotrexate and cyclosporine, which are used in cancer therapy and transplant therapy respectively,are used in lower doses for RA.and the incidense of adverse side effects is lower. Persistence in the use of DMARD is of great importance.
 
DMARDs are used to treat incurable chronic diseases when treatment will be lifelong and the number of options is limited. Typically a patient with RA will use a succession of DMARDs over the years. After an initial response,a drug is often eventually discontinued,either because of adverse side effects or loss of effect.
 
To ensure the best result,it is important to give each drug a full trial, namely,the maximum dose for sufficient time,before declaring a drug is not efficacious. There are a number of strategies for dealing with common side effects.
 
The use of combination DMARDs is now widely practised,Some physicians advocate the use of combination therapy at the onset of disease early control,with a subsequent gradual withdrawal of therapy,as necessary to maintain control. Others prefer the opposite strategy successively adding DMARDs to agents to which the patient has shown a partial response. Proponents of the latter view,believe it prevents unnecessary exposure to potentially toxic drugs of patients who may respond to single therapy
 
Commonly used combinations include hydroxychloroquine with most DMARDs,especially methotrexate. or intramuscular gold,sulfasalazine and methotrexate with or without hydroxychloroquine,and cyclosporine and methotrexate.
 
The most accurate and most often used measurement of inflammation is the sedimintation rate or "sed rate".This test is based on how quickly  red blood cells settle at the bottom of the test tube.The ESR is useful in differentiating RA from other types of arthritis. If your joints are very swollen your doctor may take a small sample from the swollen joint.Normal synovial fluid is clear,thick and oily,it becomes cloudy because it is infiltered with usually white blood cells and debris
 
Baseline laboratory evaluations should include complete blood count (CBC), platelet count,chemistery profile,RF measurement,and measurement of ESR or CRP. Evaluation of renal and hepatic function is necessary since many antirheumatic agents have renal or hepatic toxicity and may be contraindicated if these organs are impaired.
 
There's a wide variety of topical creams and gels available that provide temporarily pain relief-including a prescription cream made from the active ingredient (capsaicin) in hot chili peppers. Some creams contain the active ingrediant (acrtylsalicylic acid) in ASA,which is absorbed through your skin and should be factored into your total daily dose if you're taking ASA or ibuprofen in tablet form. Since it's difficult to calculate how much ASA you've absorbed into a cream,try to avoid using a cream and tablets on the same day. And keep in mind that all such creams are for pain relief only,they aren't effective as NSAIDs.
 
The majority of creams and gels (and liniments and poulticies)are counter irritants,which work by pitting one pain against another, inducing the body to lower its sensitivity. Applied to a painful joint,they produce a temporary local reaction that may cause skin irritation,mild swelling or a temperature change-and a lessening of pain.Most such counterirritants use heat or cold to'distract' the brain from recognizing the signal from the pain source by amplifying the nerve signals recieved by your brain's pain centres. Overwelmed by the influx of chemical messages,the brain temporarily'switches' them off,thus providing pain relief.
 
According to a 1995 ,November issue of Letters,at the University of Berkeley,clinical studies into capsaicin's use have been small and short-term,and not much is known about the effect of long-term use. Still,they note that many people find capsaicin helps. 'As the package direction should say,you need to use the cream 3 or 4 times a day,and you may not notice much improvement until you've applied the cream for a week or more. Many people can't tolerate it-skin becomes irritated.  Never use the cream under a bandage,and don't get it into your eyes. or an open cut.
 
For some people,rubbing one of these salves on a arthritic joint is as effective as the pain relief they experience from NSAIDs. Capsaicin,the alkaloid that gives chili peppers their fire,has been recruited as a counterirritant. Nonprescription salves or lotions,such as Zostrix,Capzasin-P and Capsin contains 0.025 to 0.25 % capsaicin, through a tube of cream may contain as much pure capsaicin as hundreds of chili peppers. While such creams generate a feeling of warmth on the skin,their effect is muted enough that you can apply the treatment several times a day.
 
Some promising combinations include:
 
1) Methotrexate (MTX) and Sulfasalazine (SSZ) and Hydroxychloroquine.(HCQ)
 
2) MTX and Intramuscular Gold .
 
3) MTX and Etanercept. (Enbrel )
 
4) MTX and Leflunomide ( Arava )
 
5) MTX and Infliximab. ( Remicade )
 
6) MTX and Cyclosporin has been tried ,but due to higher toxicity of cyclosporin it is not used commonly,today.
 
7) MTX and Arava ( Leflunomide ) might not work for everyone. Monitoring and selection will  vary due to differences in patient efficacy.
 
Methotrexate has become the gold standard in North America. It promises early onset of action,usually within 4 to 6 weeks. MTX is usually given as tablets,but can be given subcutaneously.
 
The effective weekly dose for a patient may be low as two 2.5 mg tablets,or as high as ten. The average is 5 tablets (12.5mg.) once a week. Because the effective dose range is so wide,its best to start low (3 tablets / week). and only slowly increase the dose by one tablet each time. changes in dose should occur no more often than every 3 weeks;once a month is the usual.
 
It is unusual to notice a good response at a fairly low dose at first,but then to require a higher dose later on to maintain that response. a complete blood count (hemoglobin,white cell and platelet counts ) is usually done every 2 weeks until the final dose is selected,then every 4 to 6 weeks Liver function test may be performed,depending on the patient situation. Some patients claim better response with the injection procedure with less side effects.
 
NSAIDs don't interact with MTX when MTX is taken in the doses recommmended; however,sulfa-containg antibiotics increase the risk of side effects and should be avoided. Side effects are ofen dealt with by decreasing the dose or temporarily stopping MTX and then restarting it.
 
Gold has the potential of disease suppression.,but it is more toxic The refular dose is (50 mg./weekly). To make sure the patient isn't sensitive to gold,two small test doses of aurothiomalate are given,one week apart. The practise in the past was to do this,once a week,until 1,000 mg. had been given,and some doctors may still do this. If the patient is no better,then they try another drug
 
The major disadavantage include the need to visit the doctor each week,the longer time for efficacy (12 to 20 weeks), Blood tests and urine tests are usually done prior to injection. Twenty weeks is a long time to wait to see if the drug works or not. If it does not work,it is valuable "wasted time" w.r.t. to the ongoing disease process.
 
Azathioprine is taken daily. The initial dose is one tablet (50 mg) and later the dose is adjusted according to the patient's weight. Later,if the patient has done well,the dose can be reduced without losing the effect. Once a regular dose has been settled on complete blood counts (CBC) are needed less frequently than with mtx and gold,but it should still be checked at least every 3 months.
 
Sulfazaline is used more in Europe. The British rank it somewhere near intramuscular gold. Its safety profile is excellent. It takes action in 2 to 3 months
 
There are some conflicting reports as to whether SSZ is useful in some of the seronegative arthritis cases, PA and AS. SSZ should be started with a low dose and gradually built up. Start with one tablet (500 mg) a day for a week,then increase the daily dose by one tablet each week until, by the fourth week the patient is taking two tablets twice a day, there are other variations to this schedule.
 
Hydroxychloroquine HCQ) is considered to be much weaker than almost all the other DMARDs(plaquenil).  It's safety profile is excellent It takes effect in 3 to 6 months ,but its long-term benifit is not so good as the others. In the case of severe RA,six months is a long time to wait,and find the drug ineffective.
 
It's very important to get a annual eye check up. The maximum daily dose is 400 mg-calculated w.r.t. bodyweight--200 mg/twice/daily.
 
Auranofin-oral gold has been proven to be a disappointment. There is little flexibility in the dose of auranofin- one 3 mg. tablet twice a day. A complete CBC and urinalysis /monthly.
 
D-penicillamine and cyclosporin is not commonly used today . With the many alternative,including the newer biologics the two are on the "back-burner" but when every thing else fails,they are available-they have higher toxicity levels,and hard to control,at times
 
The development of genetically engineered biologic agents that selectively block cytokines (anticytokine therapy) in the short term,represents a major advance in the treatment of RA.  Etanercept is a recombinant soluable TNF-fc fusion protein,and infliximab is a chimeric (mouse-human ) anti-TNF monoclono antibody.
 
Infliximab is currently recommended for use only with concomitant MTX therapy. MTX may be used with etanercept or used alone. Several randomized trials have demonstrated that patients with etanercept alone or with infliximab plus MTX have less radiographic progression after 1 year rhan patients treated with MTX alone. In the trial with patients made up of early RA patients,the symptoms and signs of RA improved more rapidly over the first 6 months,with compareable efficacy of the two agents at 12 months.
 
The ACR guidlines for monitoring liver toxicity in patients recieving MTX is that a liver biopsy should be performed in patients who develop abnormal findindings on liver function studies,that persist during treatment or upon discontinuing the drug. Liver toxicity with MTX is rare.
 
Although data from randomized trials have not shown an increased frequency of adverse effects,such as infections or malignancies,for either anti-TNF agent,concerns about the short-term and long-term safety of these agents continue. Enbrel was recently given a 5 year safety approval in clinical trials.
 
Clinical trials have demonstrated the efficacy of infliximab and etanercept in improving clinical symptoms and signs in patients with RA,according to the ACR 20,50,and ACR 70 improvement criteria. Patients with early active RA and those that had failed previous conventional therapy showed improvements. Anti-TNF agents should be used with caution in patients susceptible to infection or a history of T.B.,should be avoided in patients with significant chronic infections and should be discontinued,temporarily in all patients with acute infection
 
Postmarketing surveillance has yielded reports of septis,tuberculosis.a typical mycobacterial infections,but it not common. At this time there appears to be no need of routine laboratory testing. Not all patients will respond to TNF therapy. The main disadavantage is high cost and parental administration.
 
Minocycline have shown efficacy in certain early,milder type RA patients. Surprisingly it showed efficacy in a subset of patients who were positive for the HLA shared epitope (HLA-DR4+)(--A.S.) conclusion is further testing should be done on tetracyclines.
 
Intramuscular  gold treatment is effective,but injections are required every week for 22 weeks before less-frequent maintaince dose is started. Oral gold althought more convenient,has proved less efficacious and is not commonly used.
 
Cyclosporine is beneficial and has short-term efficacy to that of D-Pen (not used frequently). the use of cyclosporine,however,has been limited by its toxicity,expecially hypertension and dose-related renal function 20 %loss of renal function appears to be reversible for renal function loss,but not entirely. Dose calculation to avoid renal toxicity is more critical with cyclosporine than with any other DMARD. Cyclosporine plus MTX was found to be more effective than MTX alone but long-term follow up revealed the development of hypertension and elevated creatinine levels
 
Low-dose oral glucocorticoids (<10 mg of prednisone daily,or the equivalent) and local injections of glucocortoids are highly effective for relieving symptoms in patients with active RA.  A patient disabled by active polyarthritis may experience marked and rapid improvement in functional status within a matter of a short period. Frequently,disabling synovitis recurs when steriods are discontinued,even in patients who are receiving combination therapy. However, many patients are functionally dependent on steriods and continue them long-term.
 
Recent evidence suggest that low-dose glucocorticoids slow the rate of joint damage and appear to have disease-modifying potential Joint damage may increase on discontinuation, Previously it was thought they did nothing to stop disese progression.
 
The benefits of low-dose glucocorticoids,should always be weighed against their adverse effects which are well documented elsewhere.
 
 Because of its favourable efficacy and toxicity profile,low cost and established track record in the treatment of RA MTX has become the standard by which new DMARDs are evaluated. 
 
More recent (1999 ) randomized clinical trials have established the efficacy of MTX in RA, particularily in patients with more severe disease. Longitudal observational studies and randomized controlled trials show that MTX retards the progression of radiographic erosions.
 
Observational studies indicate that more than 50 % of patients who take MTX continue the drug beyond 3 years,which is longer than any other DMARD. RA patients taking MTX are more likely to discontinue treatment because of adverse reactions than because of lack of efficacy.
 
Stomatitis,nausea,diarrhea,and perhaps alopecia caused by MTX may decrease with concomittant folic acid or folinic acid treatment without significant loss of efficacy. Relative contraindications for MTX therapy are pre existing liver disease,renal impairement,significant lung disease,or alcohol abuse.
 
Since the most frequent adverse reaction in MTX is elavation of liver enzyme levels,their function must be monitored,but the risk of liver toxicity is very low
 
Clinical trials have established leflunomide as an alternate to MTX as monotherapy,especially for patients who cannot tolerate MTX  The reduction in RA disease activity and in the rate of radiologic progression achieved by leflunomide appears to be equivalent to tht of a modest dose of MTX. Leflunomide is also used in combination therapy with MTX,in the absence of a complete clinical response with full dose MTX.
 
Five percent of patients recieving leflunomide and up to 60 % of patients recieving MTX plus lefunomide have elevated liver enzyme levels
 
Also,refer to Leflunomide or Arava,Enbrel Remicade,Glucosteriods,NSAIDs and DMARDs articles on site,for more information.
 
Conventional treatment with a single DMARD often fails to adequately control clinical symptoms or to prevent disease progression  As a result rheumatologists  are increasingly prescribing combination DMARD therapy. Controversy remains whether to initiate this type of therapy in a sequential "step-up" approach in patients with persistent active disease in whom single agents have failed or whether to initiate combination therapy early in the disease course and then apply a "step-down" approach once adequate disease control is attained. In either case rheumatology referrel is strongly recommended,when considering this route.
 
Since DMARDs control rather then cure RA,the management of RA is an iterative process and patients should be periodically reassessed for evidence of disease or limitation of function with significant alteration of joint anatomy. Reconstructive surgery can be done at any point in the course of RA.
 
Some patients have resistant disease and experience a progressive course despite exhaustive trials of DMARDs,whether used alone or in combination. At each followup visit the physician must asess whether the disease is active or inactive. Symptoms of inflammatory (as contrasted with mechanical ) joint disease,which includes prolonged morning stiffness,duration of fatigue,and active joint synovitis on joint examination,indicate active disease and necessitate consideration of changing the treatment regimen
 
Occassionally,findings of the joint examinations alone may not adequately reflect disease activity and structural damage.therefore,periodic measurements of the ESR and CRP level and functional status as well as radiographic examinations of involved joints should be performed.
 
Functional  status may be determined by questionnaires such as the Arhtritis Impact Measurement Scales or the Health Assessment Questionnaire. It is important to determine whether a decline in function is the result of inflammation,mechanical damage or both,treatment strategies will differ. accordingly.
 
The American College of Rheumatology (ACR) has developed criterias for defining improvement and clinical remission in RA. These criteria is accepted world-wide in rheumatology circles.
 
People living with RA will need to become more familiar with the treatment regimen,know when therapy is working and when it is not. Familiarize themselves with side effects so that when they occur,intelligently inform their physicians as to change of dose or medication to ensure safety,health,and success of the whole treatment and managment process.
 
Instruction in joint protection,conservation of energy,and a home program of joint range of motion and strengthenining exercises are important in achieving the treatment goal of maintaining joint function. Occupational  therapy and physical therapy may help the patient who is compromised in activities of daily living.
 
Regular participation in dynamic and even aerobic conditioning programs improves joint mobility,muscle strength,aerobic fitness and function and psychological well being without increasing fatigue or joint symptoms.
 
If complete remission is not achieved, (rare )the management goals are to control disease activity,alleviate pain,maintain function for activities of daily living and work,and maximize function for activities of daily living living and work and maximize quality of life.
 
Achieving these goals challenges the skill of the rheumatologist to determine the most efficacious combination of pharmacologic therapy,which may include NSAID,DMARD(s),low-dose predisone,local injection of glucocortoid, rehabilitation support and analgesics.
 
 Given the chronic waxing and waning course of RA,a longitudal treatment plan needs to be developed and the patient should be involved in the treatment plan The discussion should include disease progression,prognosis and treatment options,taking into account the cost,adverse risk factors and comorbid conditions monitoring disease activity (i.e., ongoing disease activity after 3 months of maximum therapy ),or progressive joint damage require consideration of significant changes in the DMARD regimen.
 
If disease activity is confined to one or a few joints,then local glucocortoid injection may help. For patients with severe symptoms,systemic glucocorticoids may need to be initiated,or the dosage may need to be increased,for a short period of time.
 
Active joint disease may impair physical activity. Therefore,consultation with a physical therapist,occupational therapist and /or nurse trained in rheumatic diseases may be necessary
 
Periods of rest,job modification,time off from work,changes in occupation or termination of of work may be necessary Reconstructive surgery should be considered for patients with end-stage joint damage that is causing unacceptable pain or mobility problems.
 
The initial evaluation of the patient with RA should document symptoms of active disease (i.e. presence of joint pain,duration of morning stiffness,degree of fatigue ) functional status,objective evidence of diseae activity (i.e., synovitis, as assessed by tender swollen joint counts and the ESR or CRP level )mechanical joint problems (i.e.,loss of motion, cripitus, instability,and/or deformity ) malalignment,the presence of extraarticular disease,and the presense of radiographic damage.
 
The presence of comorbid conditions should also be assessed. The patient's and physician's global assessments of disease activity and a quantitative assessment of pain using a analog scale or other validated measure of function or quality of life are useful parameters to follow during the course of the disease.
 
The baseline laboratory evaluations should include a complete blood cell count (with white blood cell differential and platelet counts ),rheumatoid factor (RF) measurement,and measurement of ESR or CRP
 
Evaluation of renal and hepatic function is necessary,since many antirheumatic drugs cause renal or hepatic toxicity,and may be contraindictated if these organs are impaired.
 
Since the hands and feet are so frequently involved in RA,radiographs of these joints as well as other affected joints establish a baseline for future assessment of structural damage. Arresting and preventing structural damage is a primary goal of therapy.and radiographic studies of major involved joints may be neded periodically
 
Selection of the treatment regimen requires an assessment of prognosis. Poor prognosis is suggested by earlier age of disease onset,higher titer of RF,elevated ESR,and swelling of > 20 joints, Extraarticular manifestations of RA such as rheumatoid nodules,Sjogren's syndrome,episcleritis and scleritis, interstitial lung disease,pericardial involvement,systemic vasculitis and Felty's syndrome,may indicate a worse prognosis,but they have not ben widely adopted for clinical practice.
 
The ACR criteria for 20 % clinical improvement (the ACR 20) requires a 20 % improvement in the tender and swollen joint count,as well as a 20 % improvement in 3 of the following 5 parameters:
 
1) Patient's global assessment.
 
2) Physician's global assessment.
 
3) Patient's assessment of pain.
 
4) Patient assessment of degree of disability.
 
5) Patient assessment level of acute-phase reactant
 
These criteria have been expanded to include criteria for 50 % improvement measures (i.e. ACR 50,ACR 70 )> Other criteria such as the Paulus criteria have also been employed. More recently,radiographic progression (e.g.,the Sharp Score) has been utilized as a outcome measure.
 
Start by trying to find out where the individual who has rheumatoid arthritis is with the particular illness. Different things affect people in different ways. Some people may be very anxious about the future and be coping with the present very well. Others may have difficulty even thinking about how to get up in the morning and proceed with their day. Often start with where the patient is.
 
The initial thing is try to find out is whether they have support from their husband, wife, or other family members. If they're employed, does their boss understand what's going on with them? People need a sense that this illness is not going to isolate them. They need to be understood and have a feeling that other people care about them.
 
Getting support from family members and employers is very important. Oftentimes, feeling understood gratifies people so much - they feel like other people care about them. It's often very important that they discuss the frustration and the depression with their primary physician. The doctor may suggest a referral, so they can have an opportunity to really pour their heart out about what's troubling them and what they're frightened of.
 
A psychiatrist,may suggest the use of antidepressant medication, though not necessarily right away. This often can be quite helpful in lifting someone's mood and also can be helpful in terms of pain control even though it doesn't necessarily do anything for the underlying arthritis process.

Not everyone needs a antidepressent,it depends on their coping skills. It depends on what their previous history has been. If you have someone who has never been ill and all of a sudden has this diagnosis mentioned to them, the way that they react to it will often reflect how they've dealt with other traumas in their life. If there is someone who has had multiple illnesses, this additional illness can often give them an overwhelming sense of "What's going to happen to me?" and a complete loss of control.
 
People like to feel like they're in control of themselves and in control of their health. When this starts to be preyed upon, everyone feels a little bit of loss of self and somewhat of a loss of self-esteem. But we're talking about degrees here.
 
Depression and anger go hand-in-hand, as we all  know. What do you tell a person who's living with rheumatoid arthritis and who's frustrated with their inability to do the simple things that they used to be able to do?
Number one,try and empathize with them about how difficult that must be. Number two,tell them express themselves, how angry they're feeling, even if they tell the therapist they're not angry. The therapist try to get to the point where they understand that it's very normal to be angry, and they don't need to be afraid of their anger or feel guilty about their anger.
 
The therapist then work with them on how they're going to begin to get some of their expectations met and how they're going to go on in life with a more positive focus rather than being so consumed with the idea that this disease is going to take everything away from them.  "It's very normal to be angry. Patient's are encouraged to get involved in learning about their illness and in learning about good health in general."  
 
As somebody coping with diabetes, which is another long-term chronic condition, sometimes it's not the disease that’s the problem, it's the stress of coping with the disease.  It always depends on the degree of involvement and how much rheumatoid arthritis takes away from a person's everyday functioning. It is helpful is to get people involved with other rheumatoid arthritis patients so that they hear that their complaints are similar to other patients struggling with the illness. Try to encourage patients to do as many things as possible that they like to do and things that they used to do.
Patients need encouragement to get involved in learning about their illness and in learning about good health in general.
 
There are a lot of things like exercise and proper diet which we hear a lot about today that really do make some sense for people who don't have a particular illness. But especially if you have a chronic illness, that's something that you have to watch. The more you can help a person focus on the positive things about their life, the better they're going to be able to tolerate having this particular illness

Treatment Of Rheumatoid Arthritis:
 
A critical question in the long-term treatment of patients with RA is whether an aggressive,early,and intervention can provide long-term benefit in patients with RA. The results of the combination "Cobra Trial" have provided some insight with respect to this issue.
 
The initial phase of this study demonstrated that combination "step-down" therapy with predinisolone,MTX and SSZ was superior to SSZ alone,for suppressing disease activity and radiologic progression of RA ( it is questionable if SSZ alone can achieve this). Additional 4 to 5 year follow-up of these patients during treatment (all recieved "best available therapy") showed that the patients who recieved combination therapy as initial treatment had significant less disease progression than those treated with SSZ alone.
 
Thus,initial intensive combination treatment that included very short-term,high-dose corticosteriod resulted in substantial suppression of radiological progression in patients with early RA,independent of subsequent anti-rheumatic therapy.
 
The clinical results support that most patients should be initially treated with MTX ,with rapid dose titration to 20 to 25 mg/week and switched to subcutaneous administration if oral therapy is not effective. If such treatment does not yied a satisfactory response,SSZ and HCQ should be added to the regimen.
 
Biologic agents can and should be added,preferably within the first year after diagnosis if patients have not responded in a satisfactory fashion to optimal combination DMARD therapy.
 
Many RA patients will experience disease progression,particularly when treated with a single agent,and will require additional therapy to manage their clinical symptoms. A number of treatment options have proven effective for such patients,most of which will entail the continuation of MTX therapy and/or addition of other DMARDs. Both HCQ and SSZ are highly effective when used in combination with MTX and results reviewed in clinical trialss use the combination of MTX,HCQ and SSZ in patients who have had suboptimal response to MTX alone
 
Other potentially effective combinations include MTX plus cyclosporine (when other therapy fails because of the toxicity factor) or leflunomide (which will need close monitoring from adverse effects affecting the kidney which have ocurred with this combination). MTX trials have been done on MTX combined with etanercept,infliximab or DE27 (adimumab),and further trials are needed.

Leflunomide (brand name Arava) was released for treatment of rheumatoid arthritis (RA) in September 1998. Like all new medications, leflunomide was tested in clinical trials to determine its effects, good and bad, before it was released. Since it has been on the market, it has been shown to be an effective medication for rheumatoid arthritis in many patients, and is generally well tolerated.

In February 2001, the European Agency for the Evaluation of Medicinal Products reported a series of side effects affecting the liver to Aventis, the manufacturer of leflunomide. There were 296 cases of liver abnormalities, most relatively minor. However, there were 129 cases of severe side effects affecting the liver in patients with rheumatoid arthritis who were being treated with leflunomide, including 9 deaths among 15 patients with severe liver failure.

A review of information about these cases supplied by Aventis reveals that most occurred within the first 6 months of treatment, but can occur after as few as 3 days or as long as 3 years. Side effects affected men and women patients of all ages. Most patients had one or several other diseases, such as heart disease, diabetes, or viral hepatitis B or hepatitis C. Most patients were also taking other medications at the same time, which could be toxic to the liver. These include methotrexate and nonsteroidal anti-inflammatory drugs (ibuprofen, naproxen, celecoxib, rofecoxib, and many others).

There were several types of liver damage reported with the use of leflunomide. These included drug induced hepatitis, reactivation of viral hepatitis (especially hepatitis B), rapid liver failure, jaundice, enlargement of the liver, and liver cirrhosis.

The manufacturer of leflunomide, Aventis, has determined that the severe side effects could not be related to the use of leflunomide with absolute certainty, but that such a relationship also could not be excluded.

Leflunomide should be used with caution in all patients. Regular laboratory tests, including blood tests of liver function, must be done for all patients taking this medication. The tests are done more frequently at the beginning of treatment with leflunomide, usually just before starting treatment and then monthly for the first six months. They may be done somewhat less frequently after the first 6 months, perhaps every 2 months depending on how well the drug is tolerated.

Leflunomide must be used with caution in patients taking other medications that can be toxic to the liver, such as methotrexate and nonsteroidal anti-inflammatory drugs. Leflunomide should not be prescribed to patients with a past history of alcohol abuse. It should be avoided in patients who have had viral hepatitis B or C, other liver abnormalities such as cirrhosis, or past serious infections. It must not be taken by women who are pregnant because of the risk of birth defects.

If you are taking, or considering taking, leflunomide, please discuss these important issues with your physician.

Treatment for rheumatoid arthritis with disease modifying anti-rheumatic drugs (DMARDs) can be suboptimal when a single medication is used alone. Current treatment regimens incorporating multiple medications can gain better control of arthritis activity.  A major challenge facing physicians and patients with RA is the selection of an appropriate combination of DMARD medications. Clinical studies have documented the safety and effectiveness for some combinations; however, the benefit of combinations remains unstudied.

Methotrexate and leflunomide are two commonly prescribed DMARD medications used to treat RA. Both medications are thought to function by affecting DNA (the “building block” of genetic material) production. Some authorities have suggested that since methotrexate and leflunomide see function at different points in the process of DNA production, their use in combination may be beneficial. However, since these medications share some toxicities, there has been substantial concern about the safety of combining them in RA therapy. An initial open-label clinical study suggested that combining leflunomide and methotrexate was of benefit for RA patients.  This result prompted a double-blind, controlled trial of the safety and effectiveness of combining leflunomide and methotrexate for RA treatment.

A group of investigators enrolled 263 patients with RA who were already taking methotrexate as therapy for their arthritis. These patients were randomly assigned to add either leflunomide or placebo (“sugar pill”), and were examined monthly for the six-month duration of the trial. These investigators assessed both clinical response (decreased arthritis, improved laboratory parameters) and medication toxicity. 

In this trial, the addition of leflunomide to the previously prescribed methotrexate resulted in a significant decrease in RA disease activity. Specifically, 46% of patients adding leflunomide to methotrexate responded to therapy versus 19% of patients receiving methotrexate alone. A significant number of patients noted a substantial response to the addition of leflunomide.

From a safety standpoint, adverse side effects were reported frequently in both groups of patients (89% each). However, all reported adverse events were mild to moderate in intensity. Since both methotrexate and leflunomide can lead to liver damage, special attention was paid to monitoring liver toxicity. The investigators found higher rates of liver test abnormalities in patients receiving leflunomide, but in most instances these abnormalities resolved without a change in the medication dosage or other intervention.  Three patients receiving leflunomide and two patients receiving placebo required discontinuation of medication due to persistently abnormal liver laboratory tests.

From these results, the investigators conclude that the combination of methotrexate and leflunomide is both safe and effective for treatment of RA –  with the caveat that this treatment combination requires careful monitoring for toxicity. It should be noted that this trial was of relatively short duration (six months). A degree of caution remains necessary until longer-term studies are published. However, these results provide physicians and RA patients important information on treatment options when their arthritis is not satisfactorily controlled with a single DMARD medication

Rheumatoid Arthritis Warning Signs In Treatment:
 
Warning signs in treatment can represent a worsening or complications of the rheumatoid disease,side effects of medications,or a new illness or problem that is complicating the condition of patients with RA.
 
Worsening of symptoms: This includes more pain,more swelling,additional joint involvement,redness,stiffness,or limitation of function. The physician will determine  the significance. Sometimes, at the start of a new medication,some minor increase in joint problems might be occurring while the new medication is taking effect. However,worsening of symptoms,can also mean the medications are not working and they may require adjustment in dosing or a change in the medication. Each drug has a  certain "time-period" for effaciousness-expectations. The patient should ask the physician at the beginning,how long that period is.
 
If a patient has seen the physician and is started on a treatment plan is not showing improvements,but is worsening,the physician must be notified. after starting a new treatment program,it sometimes take time for the medications, physical therapy etc., to control the inflammation. The primary care-giver must decide on the on-course-current status. There are many possible side effects associated with medications used in treating rheumatoid arthritis and the patient should be aware of them that are associated with their own particular therapy.  When the side effect,or effects do occur,the doctor should be promptly be informed.
 
Rheumatoid arthritis patients often,have many health care professionals involved in the treatment plan,but there should be one, (rheumatoligist) responsible for the principle medication, (DMARD or Steriod) administeration and control. A drug that is not working after a known,trial-time-period will never work. Remember,that therapy is an individualized process in many cases,meaning one drug will work wonders for one patient, and do nothing for another.
 
A mildly elevated temperature is not unusual in a person with RA. However,a true fever, (temperature above 100.4 degrees F. or 38 degrees C.) is not expected and can represent,possible  infection. Patients are at added risk for infection because of the medications used in therapy (immune suppression etc.) and the nature of the disease.

At present, traditional DMARDs remain the first choice for monotherapy or combination treatment in patients with RA. Although the new biologic DMARDs that block the activity of tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1) have shown great promise in the treatment of RA, further evidence is needed to demonstrate their superiority over traditional DMARDs as initial therapy.
 
There are a number of key gaps in our knowledge about the new biologic agents and how they compare to traditional DMARDs. First, most patients treated in clinical practice would not meet the entry criteria employed in clinical trials of these new agents. Comparison of patients treated in practice with entry criteria for the Early Rheumatoid Arthritis (ERA) trial and the Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) trial indicate that only 31% and 5%, respectively, would have qualified for these 2 studies.
 
 A second important gap in our current data is that there has been only 1 study that directly compares a biologic against a traditional DMARD. Third, the effectiveness of biologic DMARDs has not been directly compared with those of alternative conventional DMARDs in patients who had less than optimal responses to methotrexate (MTX).  Finally, we continue to examine the long-term efficacy, safety, and cost of the new biologic treatments for RA.
 
Optimal Use of Conventional DMARDs-Methotrexate. If one accepts the view that we do not have sufficient data to abandon traditional DMARDs in favor of biologic preparations, one should then ask what is the best way to treat RA patients with conventional DMARDs?
 
It is well established that MTX has the most durable efficacy of any single traditional DMARD in individuals with RA and it is now generally accepted as the gold standard for these patients. Recently published results have shown that MTX significantly decreases the overall risk for mortality and for cardiovascular death in a cohort of 1240 patients with RA. After adjustment for baseline prognostic factors, the mortality hazard ratio for MTX use compared with no MTX was 0.4.
 
 The hazard ratios for cardiovascular death and noncardiovascular death in MTX-treated patients were 0.3 and 0.6, respectively. The potent disease-modifying activity of MTX is underscored by data from the ERA trial indicating that it is as effective as etanercept in slowing radiographic disease progression over 1 year.
 
The results from the ERA trial are also important because they demonstrated that high-dose MTX was significantly more effective than low-dose therapy for all key efficacy measures including American College of Rheumatology (ACR)-N, a continuous measure of clinical improvement derived from the ACR response criteria, the Health Assessment Questionnaire (HAQ), and Medical Outcomes Study Short Form-36 (SF-36).
 
These results support the view that the MTX dose should be increased to 20 to 25 mg/week in RA patients when necessary. Absorption of MTX may vary with oral delivery. Either intramuscular or subcutaneous administration should be used in patients who do not respond to oral therapy.
 
Neither high-dose MTX nor parenteral administration was employed in studies where patients received biologic DMARDs as a result of suboptimal responses to MTX. Folic or folinic acid should also be employed as supportive therapy to reduce toxicity in patients who experience side effects with MTX.
 
Combination therapy. The response to traditional DMARDs is often substantially enhanced by combination therapy, which has been repeatedly demonstrated to be superior to even optimal MTX monotherapy in controlled clinical trials.
 
Triple-drug therapy with MTX, sulfasalazine (SSZ), and hydroxychloroquine (HCQ) has also been shown to be significantly superior to the 2-agent combinations of MTX plus either SSZ or HCQ. This was demonstrated in a 2-year, double-blind, placebo-controlled trial of 171 RA patients.
 
Patients receiving the triple combination had the best response to therapy, with 78% achieving an ACR20 response at 2 years, compared with 60% of those treated with MTX and HCQ and 49% of those treated with MTX and SSZ. Similar trends were seen for the ACR50 response, with 55%, 40%, and 29% of patients in the 3 treatment groups, respectively, achieving these results at 2 years; and for the ACR70 response where the respective values were 26%, 16%, and 18%.
 
The sustained effectiveness of combination therapy with traditional DMARDs has been supported by the results of several long-term studies. Toxicities associated with this regimen are low with regular monitoring of patients and various laboratory parameters.
 
Aggressive early therapy. Recently updated treatment guidelines published by the ACR recommend prescribing DMARD therapy for patients with RA within 3 months of diagnosis. Selection of any pharmacotherapy is based on using the safest treatment plan that matches the aggressiveness of the disease. Agents can be used as monotherapy or in combination.
 
The effectiveness of early aggressive combination therapy is underscored by results from Calguneri and colleagues  who treated 180 patients with early active RA with 1, 2, or 3 DMARDs and followed them for 2 years. There were significant improvements in clinical and laboratory parameters in all 3 groups, but they were greatest in the patients given the 3-drug combination .
 
How effective are the traditional DMARDs versus biologic preparations? The ERA trial is the only study that has addressed this question. In the first year of this trial, 632 patients with early RA were treated with either twice-weekly subcutaneous etanercept (10 or 25 mg) or weekly oral MTX (mean dose = 19 mg/week) for 12 months. Study results showed that the effectiveness of MTX was very similar to that of etanercept.
 
There are several studies (some available only as abstracts) that have demonstrated the effectiveness of biologic DMARDs in patients who responded suboptimally to MTX (dosed at less than or equal to 20 mg/week with no patients switched from oral to either subcutaneous or intramuscular administration). These results make it difficult for the clinician to judge the relative effectiveness of the new preparations vs traditional DMARDs.
 
However, review of the literature suggests that treating patients who responded suboptimally to MTX with other traditional DMARDs or combinations of these drugs may be as effective as administration of biologic preparations.
 
Can Early Intervention Suppress Disease Progression in RA?
A critical question in the long-term treatment of patients with RA is whether an aggressive, early, and temporary intervention can provide long-term benefit in patients with this disease. The results of the Combinatietherapie Bij Reumatoide Artritis (COBRA) trial have provided some insight with respect to this issue.
 
The initial phase of this study demonstrated that step-down combination therapy with prednisolone, MTX, and SSZ was superior to SSZ monotherapy for suppressing disease activity and radiologic progression of RA. Additional 4- to 5-year follow-up of these patients during treatment (all received "best available" therapy) showed that the patients who received combination therapy as initial treatment had significantly less disease progression than those treated with SSZ alone . Thus, initial intensive combination treatment that included very short-term high-dose corticosteroids resulted in sustained suppression of radiologic progression in patients with early RA, independent of subsequent antirheumatic therapy.
 
Management of Established RA: Dealing with Treatment Failure  Many RA patients will experience disease progression, particularly when treated with any single agent, and will require additional therapy to manage their clinical symptoms. A number of treatment options have proven effective for such patients, most of which entail the continuation of MTX therapy and/or addition of other DMARDs.
 
Both HCQ and SSZ are highly effective when used in combination with MTX and results reviewed above strongly support use of the triple combination of MTX, HCQ, and SSZ in patients who have had a suboptimal response to MTX.
 
Other potentially effective combinations include MTX plus either cyclosporine or leflunomide, or MTX combined with etanercept, infliximab, or adalimumab. Comparison trials of these approaches are sorely needed.
 
The results reviewed support the view that most patients with RA should be initially treated with MTX with rapid dose titration to 20 to 25 mg/week and switched to subcutaneous administration if oral therapy is not effective. If such treatment does not yield a satisfactory response, SSZ and HCQ should be added to the regimen.
 
Biologic agents can and should be added, preferably within the first year after diagnosis, if patients have not responded in a satisfactory fashion to optimal combination DMARD therapy.